Iminium-ion activation as an efficient strategy for divergent synthesis of optically active propargylic, homopropargylic, and allenic compounds

Article abstract of DOI:10.1002/chem.200901921

Assemble and build: The strategy depicted above merges different organocatalyzed conjugate addition reactions with the Seyferth-Gilmann homologation by which diverse opti-cally active propargylic, homopropargylic and allenic products can be assembled in h

Full text of DOI:10.1002/chem.200901921

DOI: 10.1002/chem.200901921
Iminium-Ion Activation as an Efficient Strategy for Divergent Synthesis of
Optically Active Propargylic, Homopropargylic, and Allenic Compounds
Hao Jiang, Nicole Holub, Mꢀrcio W. Paix¼o, Caterina Tiberi, Aurelia Falcicchio, and
Karl Anker Jørgensen*[a]
The acetylenic motif serves as a common synthon in many
generalization leading to diversity-oriented synthesis of opti-
cally active propargylic compounds is a highly desirable and
important synthetic methodology. However, this seemingly
intuitive approach encountered unavoidable difficulties,
such as product decomposition and racemization, when sub-
stituting the a-fluorination reaction with other organocata-
lytic a-functionalizations. We then turned our attention
toward the use of iminium-ion activation assuming better
stability of the reaction intermediates and products. Herein,
we wish to report a series of chiral iminium-ion-activated
conjugate addition–homologation sequences, forming highly
enantioenriched propargylic and homopropargylic com-
pounds in a simple and benign way (Scheme 1).
[1]
À
À
C X and C C bond disconnections. Propargylic and ho-
mopropargylic compounds in particular are important as
chiral building blocks in the course of stereoselective syn-
thesis,[2] not at least owing to their transformational diversity
and condition tolerance.[3] The synthesis of propargylic and
homopropargylic compounds remains an attractive yet chal-
lenging task, pursued by many research groups. Nowadays,
modern synthesis and synthetic methods oftentimes include
new and important aspects such as time-cost control and
sustainability.[4] One of the methods to reduce time costs is
the invention of more chemospecific reactions, thereby
avoiding the use of protective groups and superfluous redox
manipulations.[5] An alternative, but equally efficient solu-
tion to the problem is the incorporation of one-pot proce-
dures[6] and entrapment of intermediates when formed,
making product isolation unnecessary. Moreover, other
issues such as structural lability, a frequent cause for product
oxidation/reduction/protections, can also be successfully pre-
vented by the use of one-pot strategies.
Organocatalysis[7] is a highly robust and reliable synthetic
tactic, impervious to air or water; therefore, being exceed-
ingly suitable for this type of “assemble and build strategy”,
in which simple and available components are assembled to
form a chiral structural skeleton, upon which molecular
complexity can be built in a one-pot fashion. Recently, we
merged the enamine-catalyzed enantioselective electrophilic
Scheme 1. Organocatalytic synthesis of optically active propargylic and
homopropargylic compounds.
fluorination of aldehydes and ACTHNUTRGNEUGNSeyferth–Gilmann homologa-
tion to form highly enantioenriched propargylic fluorides in
a one-pot reaction from commercially available reagents.[8]
Given the interests in optically active acetylenes, conceptual
Terminal propargylic epoxides[9] represent a highly privi-
leged class of synthetic intermediate, incorporated innumer-
able times in natural product synthesis or construction of
other intricate molecular structures.[9f,g] Despite the rele-
vance, routes by which they are obtained are relatively few
and often very time-consuming. The traditional strategy pro-
ceeds through the ring-closure reaction of chiral halohyd-
[a] H. Jiang, Dr. N. Holub, Dr. M. W. Paix¼o, C. Tiberi, A. Falcicchio,
Prof. Dr. K. A. Jørgensen
Center for Catalysis, Department of Chemistry
Aarhus University, 8000 Aarhus C (Denmark)
Fax : (+45)8619-6199
AHCTUNGTRENNUNG
rins,[9a,b] or by enantioselective epoxidation of enynes[9c,d]
providing the desired products. Recently, Martꢀn et al.[9e]
also reported a three-step procedure to the same class of
compound starting from pure epoxyaldehydes. We envi-
E-mail: kaj@chem.au.dk
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901921.
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Chem. Eur. J. 2009, 15, 9638 – 9641

COMMUNICATION
sioned that a more simple approach can be devised by com-
bining the organocatalyzed epoxidation reaction[7l] of a,b-
unsaturated aldehydes with the Ohira modification[10] of the
Seyfert–Gilmann homologation and the results are as out-
lined in Table 1.
Rivaling the intriguing demands for easy access to molec-
ular complexity, we aim to demonstrate the simplicity and
diversity with which our product can be transformed
(Scheme 2). Enantiomerically enriched allenes[11] are
Table 1. The organocatalytic synthesis of chiral propargylic epoxides.[a]
Scheme 2. Transformations of the propargylic epoxides. a) NH4Br, CuBr,
Cu, HBr, Et2O, À508C to À108C, 2 h; b) CS
ACHTUGNTRENUN(GN NH2)2, MeOH, RT, 1d; c)
PPh3, Br2, RT, 15 min; d) MeNH2, H2O, 60 8C, 3 d.
R (1)
d.r.[d]
Product
Yield [%][b]
ee [%][c]
1
nButyl (1a)
iPropyl (1b)
n-Hexyl (1c)
Ph (1d)
o-NO2-Ph (1e)
CH2OBn (1 f)
CO2Et (1g)
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
2a
2b
2c
2d
2e
2 f
2g
83
63
81
66
86
73
58
99
99
98
98
99
91
97
2[e]
3
AHCTUNGTREGvNNUN aluable chiral building blocks in contemporary organic syn-
thesis. Following the procedure reported by Chemla
et al.,[11c] the allenic alcohol 4 was obtained in 74% yield as
a single diastereomer. It is also known that by the addition
of a Grignard reagent, this type of bromoallenol product
can be transformed into anti-homopropargylic alcohols, a
structural motif found in ubiquitous total synthesis endeav-
ors.
To demonstrate further utility of the propargylic epoxides,
ring-opening reactions with heteroatom-centered nucleo-
philes, such as a halide or nitrogen, were conducted, provid-
ing the optically active halohydrin 5 and 1,2-aminoalcohol 6
in 94 and 55% yield, respectively. Moreover, the chiral syn-
thesis of propargylic thiiranes[12] 7 was accomplished by a
double SN2 type mechanism, giving the desired product in
55% yield based on recovered starting material and with no
loss of optical purity.
Encouraged by these results, we decided to exploit the
possibility of combining other b-heterofunctionalizations
with the in situ homologation strategy. Gratifyingly, the pre-
dicted versatility and robustness of this “assemble and
build” type tactic for synthesis of homopropargylic com-
pounds could be realized for nucleophiles such as amines,
sulfides and triazoles as described in Table 2.
Homopropargylic amines are typically prepared by a
Barbier-type reaction of propargylic bromides and aldi-
mines.[13] However, this usually requires stoichometric use of
metals such as indium. Recently, Soderquist et al. reported
an asymmetric allenylboration leading to optically active ho-
mopropargylic amines.[13b] Our approach, by merging the or-
ganocatalyzed b-amination reaction[7n,o] of a,b-unsaturated
aldehydes with the Ohira–Bestmann homologation by using
succinimide as the nucleophilic nitrogen source, allowed a
more convenient method for preparation of optically active
homopropargylic amines. Evaluating a plethora of readily
available aliphatic a,b-unsaturated aldehydes, we found the
4
5
6
7[f]
[a] Reaction performed on 0.20 mmol scale (see Supporting Information).
[b] Yields of isolated products after column chromatography. [c] ee deter-
mined by chiral stationary phase HPLC or GC. [d] Determined by NMR
spectroscopy. [e] Yield determined by NMR spectroscopy with internal
standard due to product volatility. [f] Complete trans-esterification to the
methyl ester.
The direct, one-pot formation of optically active propar-
gylic epoxides 2 is initiated by reaction of aldehydes 1 with
H2O2 catalyzed by (S)-2-[bis(3,5-bis-trifluoromethylphenyl)-
trimethylsilyloxymethyl]pyrrolidine (3)[7m] in CH2Cl2. The in-
termediate trans-epoxyaldehydes were subsequently trapped
by the Ohira–Bestmann reagent, in situ generated from di-
methyl 2-oxopropylphosphonate and 4-acetamidobenzene-
sulfonyl azide, furnishing the homologated products 2 in
high yields and excellent enantioselectivities. Both simple or
substituted alkyl and aryl side chains are allowed, furnishing
the desired trans-propargylic epoxides in 63–86% yield and
91–99% ee (Table 1, entries 1–5). When employing sub-
strates carrying other functional groups, for example, ester
(Table 1, entry 7) or hydroxybenzyl group (Table 1, entry 6),
the same levels of yield and optical purity were obtained;
however, for compound 2g, complete transesterification to
the methyl ester was accomplished. It should be noted that
the reported reaction is almost complete diastereoselective
(d.r. 20:1), and easily up-scaled to 5 mmol without affecting
the obtained yield and enantioselectivity. The absolute con-
figuration of product 2a was determined by chemical corre-
lation,[9a] confirming the (2R,3R) configuration, as expected
by comparison to the epoxyaldehyde intermediates. The re-
maining configurations are assumed by analogy.
Chem. Eur. J. 2009, 15, 9638 – 9641
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www.chemeurj.org
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K. A. Jørgensen et al.
tions[15] providing the internal homopropargylic amine 9 in
84% yield and with full conservation of the optical integrity.
Given the importance of the N-heterocyclic structure in life
science,[16] we demonstrate that enantiomerically enriched
triazoles can be obtained by “clicking” the same starting
alkyne with organic azides, as exemplified by the formation
of 10 in 80% yield and 87% ee. Alternatively, by starting
from the homopropargylic triazoles 8k and 8l, optically
active 1,2-ditriazoles (11a and 11b) with differentiated sub-
stitution pattern were obtained (Scheme 3).
Table 2. Scope of the organocatalytic synthesis of diverse homopropar-
gylic compounds.[a]
R (1)
X
Product Yield ee
[%][b] [%][c]
1
2
3
4
n-butyl (1a)
n-propyl (1i)
CH2OBn (1 f)
ethyl (1h)
suc
suc
suc
suc
suc
suc
8a
8b
8c
8d
ent-8d
8e
8 f
43
41
40
44
42
43
48
30
34
48
44
47
49
87
87
85
85
5[d] ethyl (1h)
À85
6
7
8
n-heptyl (1j)
88
cis-(CH2)2CH=CHC2H5 (1k) suc
(CH2)2Ph (1 L) suc
85
88
89
85
79
81
80
G
8g
9
i-propyl (1b)
Ph (1d)
i-propyl (1b)
ethyl (1h)
tBuSH 8h
tBuSH 8i
triaz
triaz
triaz
10
11
12
13
Scheme 3. Transformations of the homopropargylic compounds. NHPg=
succinimide. a) CuI, [PdACHTUNGTRNEG(UN PPh3)4], p-Br-PhI, Et3N, 60 8C, 4 h; b) sodium as-
corbate, CuSO4, PhSCH2N3, H2O/tBuOH, RT, overnight.
8j
8k
8l
n-propyl (1i)
[a] Reaction performed on 0.20 mmol scale, for each specific reaction
condition, see the Supporting Information; Nuc=nucleophile, suc=succi-
nimide; triaz=1,2,4-triazole. [b] Yields of isolated products after column
chromatography. [c] ee determined by chiral stationary phase HPLC.
[d] The enantiomer of catalyst 3 was used.
In summary, we have demonstrated that the iminium-ion
activation mode can be conceptually extended to a highly
efficient “assemble and build strategy” for divergent synthe-
sis of chiral propargylic, homopropargylic, and allenic com-
pounds. The structural types produced by the reactions de-
scribed in this communication include propargylic epoxides
and thiiranes; homopropargylic amines, sulfides, and tria-
zoles; allenic alcohols, click and Sonogashira adducts, all de-
rived entirely from readily available starting materials. The
flexibility with which organocatalyzed functionalizations can
be joined with the Ohira–Bestmann homologation reaction
should certainly facilitate new reaction development leading
to generation of other synthetically relevant compounds.
reaction to be unbiased to chain size (Table 2, entries 1, 2,
and 4–6) or saturation (Table 2, entry 7) providing the de-
sired optically active products 8a, 8b, and 8d–8 f in moder-
ate to good yields and high enantioselectivities. For sub-
strates carrying functionalities such as a hydroxybenzyl
(Table 2, entry 3) or a phenyl group (Table 2, entry 8), the
reaction also proceeded smoothly and in 85–88% ee. The
preparation of homopropargylic sulfides was achieved using
tert-butyl sulfide as nucleophile. Significantly, in this case
both aliphatic (Table 2, entry 9) and aromatic (entry 10) sub-
stituents were tolerated affording the products 8h and 8i in
34–48% yield and 85–89% ee. The low yield in the case of
(E)-4-methylpent-2-enal results mainly from the highly vola-
tile nature of the product. Finally, 1,2,4-triazole could also
be included as reaction partner giving rise to the synthesis
of homopropargylic N-heterocycles 8j–8l. However, in this
case, pre-prepared Ohira–Bestmann reagent was used to
combat the diminishing yields obtained from the typical in
situ generation method. As a proof of concept, three alde-
hydes with linear or branched side chains were transformed
into the requisite products 8j–8l in 44–49% yield and 79–
81% ee.
Acknowledgements
This work was made possible by a grant from The Danish National Re-
search Foundation, OChemSchool, and Carlsberg Foundation. N.H.
thanks Deutsche Forschungsgemeinschaft. A.F. thanks MIUR (Rome)
and University of Bari. C.T. thanks MIUR and University of Florence.
Keywords: allenes · asymmetric catalysis · homopropargylic
compounds · organocatalysis · propargylic compounds
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Received: July 10, 2009
Published online: August 19, 2009
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